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J. Biol. Chem., Vol. 279, Issue 26, 27472-27481, June 25, 2004

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Aberrant Polycystin-1 Expression Results in Modification of Activator Protein-1 Activity, whereas Wnt Signaling Remains Unaffected^*

Ngoc Hang Le, Paola van der Bent, Gerwin Huls, Marc van de Wetering, Mahmoud Loghman-Adham¶, Albert C. M. Ong||, James P. Calvet**, Hans Clevers, Martijn H. Breuning, Hans van Dam, and Dorien J. M. Peters

From the Departments of Human Genetics and Molecular Cell Biology, Leiden University Medical Center, Leiden 2333 AL, The Netherlands, the Department of Immunology, Utrecht University Medical Center, Utrecht 3508 AB, The Netherlands, the ^**Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas 66160, the ^||Sheffield Kidney Institute, Sheffield University, Sheffield S5 7AU, United Kingdom, and ^¶Department of Pediatrics and Pediatric Research Institute, Saint Louis University, St. Louis, Missouri 63104

Polycystin-1, the polycystic kidney disease 1 gene product, has been implicated in several signaling complexes that are known to regulate essential cellular functions. We investigated the role of polycystin-1 in Wnt signaling and activator protein-1 (AP-1) activation. To this aim, a membrane-targeted construct encoding the conserved C-terminal region of mouse polycystin-1 reported to mediate signal transduction activity was expressed in human embryonic and renal epithelial cells. To ensure specificity and minimal cotransfection effects, we focused our study on the endogenous proteins that actually transduce the signals, -catenin and T-cell factor/lymphoid-enhancing factor for Wnt signaling and (phosphorylated) c-Jun, ATF2, and c-Fos for AP-1. Our data indicate that the C-terminal region of polycystin-1 activates AP-1 by inducing phosphorylation and expression of at least c-Jun and ATF2, whereas c-Fos was not affected. Under our experimental conditions, polycystin-1 did not modulate Wnt signaling. AP-1 activity was aberrant in human autosomal dominant polycystic kidney disease (ADPKD) renal cystic epithelial cells and in renal epithelial cells expressing transgenic full-length polycystin-1, resulting in decreased Jun-ATF and increased Jun-Fos activity, whereas Wnt signaling remained unaffected. Since our data indicate that aberrant polycystin-1 expression results in altered AP-1 activity, polycystin-1 may be required for adequate AP-1 activity.

Received for publication, November 6, 2003 , and in revised form, April 5, 2004.

^* This work has been funded by Dutch Kidney Foundation Project 00.1905 and by Netherlands Organization for Scientific Research Project 015.000.54. Work performed at the laboratory of A. Ong was supported by the National Kidney Research Fund and Wellcome Trust. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Leiden University Medical Center, Department of Human Genetics, Sylvius Laboratories, Wassenaarseweg 72, 2333 AL Leiden, The Netherlands. Tel.: 31-71-527-6048; Fax: 31-71-527-6075; E-mail: D.J.M.Peters{at}lumc.nl.

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